JPH07145082A - Enteric capsule - Google Patents

Abstract

PURPOSE:To prepare an enteric capsule comprising a content coated with a coating film base material produced by crosslinking gelatin and carrageenan with ions. CONSTITUTION:Fats and oils containing unsaturated fatty acids as a content are coated with a coating film base material to provide an enteric capsule. The coating film base material is produced by mixing 100 pts. of gelatin, 1-40 pts. of carrageenan and a proper amount of water, adjusting the pH of the mixture to 3-5, and subsequently crosslinking the adjusted mixture with ions at 60-90 deg.C. The crosslinking of the gelatin and the carrageenan enables to obtain the enteric capsule coating base material which does not cause the mutual adhesion of the capsules even at high temperatures in the summer, is not dissolved in gastric juice, but is dissolved in intestinal juice. This capsule coating film base material has a high gas-barrier property and enables to produce soft capsules, hard capsules and seamless capsules.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to enteric-coated capsules, and more particularly to enteric-coated capsules containing fats and oils containing unsaturated fatty acids as health foods or pharmaceuticals.

[0002]

2. Description of the Related Art Conventionally, many techniques relating to various capsules containing medicines and health foods have been reported. Among them, most of the capsule techniques containing gelatin as a main component are intended to manufacture capsules having excellent properties by mixing this with other substances to compensate for the defects of gelatin. For example, in JP-A-5-4914,
It has been disclosed that gelatin is mixed with dietary fiber to prevent the adhesion of capsules to each other, and JP-A-5-65222 discloses that capsules are coated with pullulan to enhance gas barrier properties. Is disclosed.

Further, in JP-A-4-27352, gelatin is mixed with alginic acid to cause calcium cross-linking,
A number of patent publications have been published, including the disclosure of capsules with enteric properties. In addition to this, a method of using carrageenan as a capsule coating base material without using gelatin at all (JP-A-61-10508), alginic acid,
A technique using methoxy pectin and the like (Japanese Patent Laid-Open No. 61-44810) is also disclosed.

[0004]

Gelatin, which has long been used as a capsule base material for capsules, is widely used as a base material that is excellent in plasticity, safe, and easy to take. However, since gelatin itself has a low melting point, some capsules remain attached in the summer when the temperature is high, and it is not enteric because it dissolves in gastric juice. Therefore, a method of mixing other substances has been attempted as a method of improving the property of gelatin which is easily dissolved in water and heat, which is a drawback of gelatin, by utilizing the excellent properties of gelatin as it is, but it should be satisfied. No results have been obtained.

As an ideal capsule, it is desired to satisfy the following conditions. (1) It is plastic and can be molded into any shape. (2) The surface of the capsule is dry after molding and does not stick to each other, and it can be stored for a long time. (3) Do not react with the contents to be encapsulated and never dissolve in each other. (4) Even if it is taken by humans, it should not show any harmful effects. (5) It has a high gas barrier property to prevent entry of oxygen and water vapor in the air. (6) For example, it dissolves at a desired place such as stomach or intestine and releases the contents. However, when the present inventors retested the above-mentioned conventional technique, none of them satisfied the conditions of the ideal capsule. And although gelatin has many of the above conditions, the biggest drawback is that it is not enteric coated. Furthermore, in capsules containing fats and oils containing unsaturated fatty acids, the gas barrier of the coating substrate is It is necessary to have high quality.

The present invention has been made in view of the above problems relating to capsules containing medicines and health foods, and an object thereof is enteric coating without causing the capsule coating base material to dissolve in gastric juice. The object of the present invention is to provide an enteric-coated capsule which is composed of a film base material which does not adhere to each other even when the temperature rises in the summer and has a high gas barrier property.

[0007]

Means and Actions for Solving the Problems The inventors of the present invention have conducted various researches on the means for achieving the above-mentioned objects, and as a result, utilize the excellent properties of gelatin as a method for imparting enteric properties. We focused on ionically cross-linking gelatin and carrageenan. That is, the present inventors have focused on the fact that gelatin is a high molecular substance and have many free radicals in the molecule, and a method of increasing the melting point and modifying the solubility without largely changing the inherent properties of gelatin. The free residue of gelatin, C, was investigated.
It was revealed that cross-linking the OOH group, NH ₂ group and OH group is effective for increasing the melting point and modifying the solubility. It has been found that the properties of gelatin can be easily improved by ion-crosslinking the NH ₂ group of gelatin and the SO ₃ group of carrageenan.

The present invention is based on the above findings,
The gist of the invention is an enteric-coated capsule characterized in that the contents are encapsulated by a coating base material obtained by adding 1 to 40 parts of carrageenan to 100 parts of gelatin and crosslinking.

The form of the enteric capsule of the present invention is
There is no particular limitation, and it is one kind selected from soft capsules, hard capsules, and seamless capsules, and the manufacturing method thereof is not particularly limited, and the forming mold is dipped in the film base solution and applied to the mold. Hard capsules made by drying the film. Soft capsules made by the rotary drum punching method and the rotary method. Then, a seamless capsule is manufactured by a method known as a dropping method, a nozzle orifice method, a vibration method, or the like. Examples of the contents of the capsule to be encapsulated with the film base include fats and oils containing unsaturated fatty acids, which are attracting attention as health foods and pharmaceuticals.

Next, the coating substrate used for the enteric coated capsule according to the present invention is obtained by cross-linking gelatin and carrageenan, and its properties and production method will be described below. The pH of the aqueous gelatin solution is p below the isoelectric point.
When adjusted to H, the NH ₂ group removes one H and becomes NH ⁺ , which charges positively. On the other hand, the SO ₃ group of carrageenan becomes SO ₃ ⁻ and is negatively charged, so that ionic crosslinking is easily performed. The melting point of the mixed gel of gelatin and carrageenan varies greatly depending on the degree of crosslinking between the two. That is, as shown in FIG. 1, the melting point of this gel rises in proportion to the degree of crosslinking. When the melting point is 50 ° C. or higher, the capsule coating substrate produced using this gel is
They do not stick to each other even in the summer.

Next, the change in water solubility of the above crosslinked gel will be described. It is expected in advance that free residues such as COOH, NH ₂ and OH of gelatin and SO _{3 of} carrageenan are polar, and the more they are, the higher the water solubility is, and the less, the less water solubility is. Therefore, NH of gelatin
Cross-linking the _two groups with the carrageenan SO ₃ group reduces the water solubility. The bondability between the two largely depends on the pH of the solution. That is, if the pH becomes low, NH ⁺
Reduction is promoted, SO ₃ ^- is the degree of crosslinking and increases, conversely, pH
The higher the value, the more NH ₂ and the lower the degree of crosslinking.

[0012] With the above-mentioned properties, the degree of crosslinking is increased in gastric juice having a low pH, so that the water solubility is reduced. On the other hand, intestinal juice has a pH
Is higher and the water solubility is higher. Therefore, this relationship is advantageous for cross-linking gelatin and carrageenan to prepare a coating substrate for enteric coated capsules. Here, the results of experiments on the solubility of the capsule coating substrate of the present invention in artificial gastric juice and artificial intestinal juice are shown in FIG.
It is shown in (1) and Fig. 2 (2). As can be seen from the figure, in the artificial gastric juice, the conventional capsule coating substrate of gelatin alone dissolves within 90 minutes, but the degree of crosslinking according to the present invention is 20% or more (the parentheses of each diagram in FIG. 2). Numerical values in the above indicate the degree of cross-linking (%), but the coating base materials hardly dissolve. On the other hand, it is found that all of them dissolve in the artificial intestinal fluid, and the dissolution time is proportional to the degree of crosslinking.

As described above, according to the present invention, by cross-linking gelatin and carrageenan, the capsules do not adhere to each other even when the temperature rises in summer, and the capsules dissolve in the intestinal fluid without dissolving in the gastric juice. That is, a so-called enteric capsule film base material can be obtained.

Next, a method for preparing an enteric capsule film base material by crosslinking gelatin and carrageenan will be described. In high molecular substances such as gelatin and carrageenan, the molecules are entangled with each other and crosslinked even if the aqueous solution of both is mixed and vigorously mixed without pH adjustment or heating. The conditions for cross-linking vary depending on stirring, pH adjustment, heating, and the mixing ratio of the two. Cross-linking occurs in a wide range, but considering the possibility of industrial production of capsule manufacturing, the mixing ratio of gelatin and carrageenan is It is desirable to mix 1 to 40 parts of carrageenan with 100 parts of gelatin, but the mixing ratio is 1 gelatin.
When the amount of carrageenan is more than 30 parts with respect to 00 parts, the viscosity of the mixed gel is increased and the workability is significantly deteriorated. Therefore, in order to improve the productivity, the mixing ratio of gelatin and carrageenan is preferably 25 parts or less of carrageenan per 100 parts of gelatin.

By lowering the mixing ratio of carrageenan to gelatin, adjusting the pH to 3 to 5, heating to 60 to 90 ° C. for 10 minutes or more, and stirring the mixture, a mixed gel having a relatively low viscosity is obtained. By using this as a capsule coating base material and the contents such as fats and oils containing unsaturated fatty acids to produce soft capsules, hard capsules, and seamless capsules by the above-mentioned production method, etc., the productivity on an industrial scale is improved. Can be increased. Then, regarding the seamless capsule containing the fat and oil containing the unsaturated fatty acid produced as described above and the conventional gelatin seamless capsule, the change with time of the peroxide value was 40 ° C. and the relative humidity was 0%. When measured and compared over a week, the results shown in FIG. 3 were obtained. As is clear from this figure, according to the present invention, it is possible to obtain an enteric-coated capsule made of a coating material having a high gas barrier property.

[0016]

EXAMPLES The present invention will be described below based on examples. Example 1. 100 g of gelatin to 25 g of carrageenan
r and water 375 gr were added and mixed homogeneously, the pH was adjusted to 3, and the mixture was stirred for 10 minutes while heating to 85 ° C.
A crosslinked gel having a degree of crosslinking of 45% was prepared at 20,000 cp. Using this crosslinked gel as a coating substrate solution, a hard capsule having a coating thickness of 23 μm was manufactured by a dipping treatment method which is a conventional manufacturing method of a hard capsule. The hard capsules obtained here were tested for disintegration in comparison with conventional gelatin hard capsules. Based on the disintegration test method of the Japanese Pharmacopoeia, the disintegration state was observed in artificial gastric juice and artificial intestinal fluid at a temperature of 37 ° C., and the following results were obtained. Artificial gastric juice (pH 1.2) result Capsule of the present invention Only swelling after about 2 hours or more Conventional capsule Disintegrate in about 15 minutes Artificial intestinal fluid (pH 8.3) Result Capsule of the present invention Disintegrate in about 15 minutes Conventional capsule Separation and disintegration in about 15 minutes

Example 2 To 100 gr of gelatin, 15 gr of carrageenan and 385 gr of water were added and mixed homogeneously.
The pH was adjusted to 3.5, and the mixture was stirred for 10 minutes while warming to 85 ° C to prepare a crosslinked gel having a crosslinking degree of 40%. Using this crosslinked gel as a coating substrate solution, a soft capsule having a coating rate of 30 w / w% and a coating thickness of 400 μm was manufactured by a punching method using an oval type rotary drum. The soft capsules obtained here were tested for adhesion in comparison with conventional gelatin soft capsules. As a test method, 10 oval capsule samples were randomly placed in a glass sample bottle, and the bottle mouth was opened.
Put the sample in a thermo-hygrostat at a temperature of 40 ° C and a relative humidity of 100%, leave it for 24 hours, and then take it out, place the glass sample bottle on a desk and set the number of capsules dropped from the glass sample bottle at that time. Measured. The result is
10 soft capsules according to the present invention and 0 conventional gelatin soft capsules.

Example 3 To 100 gr of gelatin, 10 gr of carrageenan and 390 gr of water were added and mixed homogeneously.
The pH was adjusted to 3.5, and the mixture was stirred for 10 minutes while warming to 85 ° C to prepare a crosslinked gel having a crosslinking degree of 25%. By using this cross-linked gel as a coating substrate solution by the double nozzle method,
A seamless capsule having a particle size of 1 mm was produced. The seamless capsules obtained here were tested for disintegration in comparison with conventional gelatin seamless capsules. Based on the disintegration test method of the Japanese Pharmacopoeia, the disintegration state was observed in artificial gastric juice and artificial intestinal fluid at a temperature of 37 ° C., and the following results were obtained. Artificial gastric juice (pH 1.2) result Capsule of the present invention Only swelling after about 2 hours or more Conventional capsules Disintegrate almost 100% in about 5 minutes Artificial intestinal fluid (pH 8.3) Result Capsule of the present invention Disintegrate in about 5 minutes Conventional capsule disintegrated in about 5 minutes

[0019]

EFFECTS OF THE INVENTION Since the capsule film base material according to the present invention is obtained by crosslinking gelatin and carrageenan, the capsules do not adhere to each other even when the temperature rises in the summer and are not dissolved by gastric juice. It has the property of being dissolved by intestinal fluid, and can be obtained as a capsule in which the contents are encapsulated by a so-called enteric capsule film base material. In addition, since the coating film base material of the capsule according to the present invention has a high gas barrier property and is prepared from a mixed gel having a relatively low viscosity, it contains an oil or fat containing an unsaturated fatty acid as a content and is enteric coated. Soft capsules, hard capsules, and seamless capsules can be produced, and productivity can be increased.

[Brief description of drawings]

FIG. 1 is a diagram showing the relationship between the degree of crosslinking and the melting point of a mixed gel of gelatin and carrageenan.

2 (1) and 2 (2) are diagrams showing the solubility of the capsule coating substrate of the present invention in artificial gastric juice and artificial intestinal fluid, respectively.

FIG. 3 is a diagram showing the results of measuring the time-dependent change in peroxide value of seamless capsules according to the present invention and conventional gelatin seamless capsules.

[Explanation of symbols]

Numerical values in parentheses relating to each diagram in FIG. 2 indicate% crosslinking.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display area A61K 47/36 D // (A61K 47/42 47:36)

Claims (3)

[Claims] 1. An enteric-coated capsule characterized in that the contents are encapsulated by a coating base material obtained by adding 1 to 40 parts of carrageenan to 100 parts of gelatin and crosslinking the same. 2. A mixture of 1 to 40 parts of carrageenan and 100 parts of gelatin and an appropriate amount of water are mixed homogeneously, the pH of the mixture is adjusted to 3 to 5, and further heated to 60 to 90 ° C. An enteric-coated capsule characterized in that the contents are encapsulated by a coating base material obtained by stirring and cross-linking the contents. 3. The enteric-coated capsule according to claim 1, wherein the content to be encapsulated contains an oil or fat containing an unsaturated fatty acid.